Cardiac Resynchronization With Sequential Biventricular Pacing for the Treatment of Moderate-to-Severe Heart Failure

ObjectivesThe InSync III study evaluated sequential cardiac resynchronization therapy (CRT) in patients with moderate-to-severe heart failure and prolonged QRS.BackgroundSimultaneous CRT improves hemodynamic and clinical performance in patients with moderate-to-severe heart failure (HF) and a wide QRS. Recent evidence suggests that sequentially stimulating the ventricles might provide additional benefit.MethodsThis multicenter, prospective, nonrandomized, six-month trial enrolled a total of 422 patients to determine the effectiveness of sequential CRT in patients with New York Heart Association (NYHA) functional class III or IV HF and a prolonged QRS. The study evaluated: whether patients receiving sequential CRT for six months experienced improvement in 6-min hall walk (6MHW) distance, NYHA functional class, and quality of life (QoL) over control group patients from the reported Multicenter InSync Randomized Clinical Evaluation (MIRACLE) trial; whether sequential CRT increased stroke volume compared to simultaneous CRT; and whether an increase in stroke volume translated into greater clinical improvements compared to patients receiving simultaneous CRT.ResultsInSync III patients experienced greater improvement in 6MHW, NYHA functional class, and QoL at six months compared to control (all p < 0.0001). Optimization of the sequential pacing increased (median 7.3%) stroke volume in 77% of patients. No additional improvement in NYHA functional class or QoL was seen compared to the simultaneous CRT group; however, InSync III patients demonstrated greater exercise capacity.ConclusionsSequential CRT provided most patients with a modest increase in stroke volume above that achieved during simultaneous CRT. Patients receiving sequential CRT had improved exercise capacity, but no change in functional status or QoL

Effect of increased influenza and pneumococcal vaccine coverage on the burden of influenza among elderly people in Hong Kong versus Brisbane: abridged secondary publication

1. Influenza and pneumococcal vaccine uptake in older adults of Hong Kong has dramatically increased since the SARS outbreak in 2003. This enables estimation of the effect of increased vaccine coverage by comparing the relative change in influenza disease burden with Brisbane, where vaccine coverage remained stable before and after 2003. 2. Compared with the low vaccination period (preSARS), during the first 6 years of high vaccination (post-SARS), influenza-associated excess rates of cardio-respiratory disease, stroke, and ischaemic heart diseases mortality decreased more in Hong Kong than in Brisbane. 3. After the 2009 H1N1 pandemic, excess rates of all-causes mortality increased in Hong Kong but to a lesser extent than in Brisbane. 4. This study provides limited evidence that markedly increased vaccination rates have reduced influenza disease burden in elderly people of Hong Kong.This study was supported by the Health and Medical Research Fund, Food and Health Bureau, Hong Kong SAR Government (#13121282). The full report is available from the Health and Medical Research Fund website (https://rfs1.fhb.gov.hk/index.html)

Population-based plasma lipidomics reveals developmental changes in metabolism and signatures of obesity risk : a mother-offspring cohort study

Publisher Copyright: © 2022, The Author(s).Background: Lipids play a vital role in health and disease, but changes to their circulating levels and the link with obesity remain poorly characterized in expecting mothers and their offspring in early childhood. Methods: LC-MS/MS-based quantitation of 480 lipid species was performed on 2491 plasma samples collected at 4 time points in the mother-offspring Asian cohort GUSTO (Growing Up in Singapore Towards healthy Outcomes). These 4 time points constituted samples collected from mothers at 26–28 weeks of gestation (n=752) and 4–5 years postpartum (n=650), and their offspring at birth (n=751) and 6 years of age (n=338). Linear regression models were used to identify the pregnancy and developmental age-specific variations in the plasma lipidomic profiles, and their association with obesity risk. An independent birth cohort (n=1935), the Barwon Infant Study (BIS), comprising mother-offspring dyads of Caucasian origin was used for validation. Results: Levels of 36% of the profiled lipids were significantly higher (absolute fold change > 1.5 and Padj < 0.05) in antenatal maternal circulation as compared to the postnatal phase, with phosphatidylethanolamine levels changing the most. Compared to antenatal maternal lipids, cord blood showed lower concentrations of most lipid species (79%) except lysophospholipids and acylcarnitines. Changes in lipid concentrations from birth to 6 years of age were much higher in magnitude (log2FC=−2.10 to 6.25) than the changes observed between a 6-year-old child and an adult (postnatal mother) (log2FC=−0.68 to 1.18). Associations of cord blood lipidomic profiles with birth weight displayed distinct trends compared to the lipidomic profiles associated with child BMI at 6 years. Comparison of the results between the child and adult BMI identified similarities in association with consistent trends (R2=0.75). However, large number of lipids were associated with BMI in adults (67%) compared to the children (29%). Pre-pregnancy BMI was specifically associated with decrease in the levels of phospholipids, sphingomyelin, and several triacylglycerol species in pregnancy. Conclusions: In summary, our study provides a detailed landscape of the in utero lipid environment provided by the gestating mother to the growing fetus, and the magnitude of changes in plasma lipidomic profiles from birth to early childhood. We identified the effects of adiposity on the circulating lipid levels in pregnant and non-pregnant women as well as offspring at birth and at 6 years of age. Additionally, the pediatric vs maternal overlap of the circulating lipid phenotype of obesity risk provides intergenerational insights and early opportunities to track and intervene the onset of metabolic adversities. Clinical trial registration: This birth cohort is a prospective observational study, which was registered on 1 July 2010 under the identifier NCT01174875.Peer reviewe

Optical Propagation and Communication

Contains summary of research and reports on four research projects.National Science Foundation (Grant ECS81-20637)U.S. Navy - Office of Naval Research (Contract N00014-81-K-0662)Maryland Procurement Office (Contract MDA904-84-C-6037)U.S. Army Research Office - Durham (Contract DAAG29-80-K-0022)U.S. Army Research Office - Durham (Contract DAAG29-84-K-0095)U.S. Navy - Office of Naval Research (Contract N00014-80-C-0941

Optical Propagation and Communication

Contains research objectives and reports on four research projects.National Science Foundation (Grant ECS 85-09143)Maryland Procurement Office (Contract MDA 904-84-C-6037)National Science Foundation (Grant ECS 84-15580)U.S. Army Research Office - Durham (Contract DAAG29-84-K-0095)U.S. Navy - Office of Naval Research (Contract N00014-80-C-0941

Optical Propagation and Communication

Contains research objectives and reports on six research projects.National Science Foundation (Grant ECS 85-09143)Maryland Procurement Office (Contract MDA 904-84-C-6037)Maryland Procurement Office (Contract MDA 904-87-C-4044)National Science Foundation (Grant ECS 84-15580)National Science Foundation (Grant INT-86-14329)U.S. Navy - Office of Naval Research (Contract N00014-87-G-0198)U.S. Army Research Office - Durham (Contract DAAG29-84-K-0095)U.S. Army Research Office - Durham (Contract DAALO3-87-K-0117)U.S. Navy - Office of Naval Research (Contract N00014-80-C-0941_U.S. Air Force - Office of Scientific Research (Contract F49620-87-C-0043

Deleted in Liver Cancer 1 (DLC1) Negatively Regulates Rho/ROCK/MLC Pathway in Hepatocellular Carcinoma

Aims: Deleted in liver cancer 1 (DLC1), a member of RhoGTPase activating protein (GAP) family, is known to have suppressive activities in tumorigenicity and cancer metastasis. However, the underlying molecular mechanisms of how DLC1 suppresses cell motility have not been fully elucidated. Rho-kinase (ROCK) is an immediate down-stream effector of RhoA in mediating cellular cytoskeletal events and cell motility. In the present study, we aimed to investigate the effects of DLC1 on Rho/ROCK signaling pathway in hepatocellular carcinoma (HCC). Methodology/Principal Findings: We demonstrated that DLC1 negatively regulated ROCK-dependent actomyosin contractility. From immumofluorescence study, we found that ectopic expression of DLC1 abrogated Rho/ROCK-mediated cytoskeletal reorganization including formation of stress fibers and focal adhesions. It also downregulated cortical phosphorylation of myosin light chain 2 (MLC2). These inhibitory events by DLC1 were RhoGAP-dependent, as RhoGAP-deficient mutant of DLC1 (DLC1 K714E) abolished these inhibitory events. In addition, from western study, DLC1 inhibited ROCK-related myosin light chain phosphatase targeting unit 1 (MYPT1) phosphorylation at Threonine 853. By examining cell morphology under microscope, we found that ectopic expression of dominant-active ROCK released cells from DLC1-induced cytoskeletal collapse and cell shrinkage. Conclusion: Our data suggest that DLC1 negatively regulates Rho/ROCK/ MLC2. This implicates a ROCK-mediated pathway of DLC1 in suppressing metastasis of HCC cells and enriches our understanding in the molecular mechanisms involved in the progression of hepatocellular carcinoma. © 2008 Wong et al.published_or_final_versio

Is respiratory viral infection really an important trigger of asthma exacerbations in children?

We performed a prospective cohort study from September 2003 to December 2004 to delineate attributing the effect of different respiratory viral infections including newly discovered ones to asthma exacerbations in children in Hong Kong. One hundred and fourteen children aged 6–14 years with chronic stable asthma and on regular inhaled steroid were monitored for respiratory symptoms over a full calendar year from recruitment. They would attend the study clinic if peak expiratory flow rate decreased to below 80% of their baselines, if they met a predefined symptom score, or if parents subjectively felt them developing a cold. Virological diagnosis using virus culture, antigen detection, and polymerase chain reaction methods on nasal swab specimens would be attempted for all these visits irrespective of triggers. Physician diagnosed outcome of each episode was documented. Three hundred and five episodes of respiratory illnesses were captured in the cohort. Nasal specimens were available in 166 episodes, 92 of which were diagnosed as asthma exacerbations, and 74 non-asthma related episodes. Respiratory viruses were detected in 61 of 166 episodes (36.7%). There was no significant difference in virus detection rate between asthma exacerbations (32 out of 97 episodes, 34.8%) and non-asthma respiratory illnesses (29 out of 79 episodes, 39.2%). Although newly discovered respiratory viruses were identified in these episodes, rhinovirus was the commonest organism associated with both asthma exacerbations and non-asthma related episodes. Plausible explanations for much lower virus detection rate than previously reported include improved personal hygiene and precautionary measures taken during respiratory tract infections in the immediate post-severe acute respiratory syndrome period together with a significant contribution of other adverse factors like environmental air pollution. We conclude that not all viral infections in children with asthma lead to an asthma exacerbation and the attributing effect of different triggers of asthma exacerbations in children vary across different time periods and across different localities

Opposing roles for JNK and Aurora A in regulating the association of WDR62 with spindle microtubules

WD40-repeat protein 62 (WDR62) is a spindle pole protein required for normal cell division and neuroprogenitor differentiation during brain development. Microcephaly-associated mutations in WDR62 lead to mitotic mislocalization, highlighting a crucial requirement for precise WDR62 spatiotemporal distribution, although the regulatory mechanisms are unknown. Here, we demonstrate that the WD40-repeat region of WDR62 is required for microtubule association, whereas the disordered C-terminal region regulates cell-cycledependent compartmentalization. In agreement with a functional requirement for the WDR62-JNK1 complex during neurogenesis, WDR62 specifically recruits JNK1 (also known as MAPK8), but not JNK2 (also known as MAPK9), to the spindle pole. However, JNKmediated phosphorylation of WDR62 T1053 negatively regulated microtubule association, and loss of JNK signaling resulted in constitutive WDR62 localization to microtubules irrespective of cell cycle stage. In contrast, we identified that Aurora A kinase (AURKA) and WDR62 were in complex and that AURKA-mediated phosphorylation was required for the spindle localization of WDR62 during mitosis. Our studies highlight complex regulation of WDR62 localization, with opposing roles for JNK and AURKA in determining its spindle association

Deleted in Liver Cancer 1 (DLC1) Utilizes a Novel Binding Site for Tensin2 PTB Domain Interaction and Is Required for Tumor-Suppressive Function

Background: Deleted in liver cancer 1 (DLC1) is a Rho GTPase-activating protein (RhoGAP) frequently deleted and underexpressed in hepatocellular carcinoma (HCC) as well as in other cancers. Recent independent studies have shown interaction of DLC1 with members of the tensin focal adhesion protein family in a Src Homology 2 (SH2) domain-dependent mechanism. DLC1 and tensins interact and co-localize to punctate structures at focal adhesions. However, the mechanisms underlying the interaction between DLC1 and various tensins remain controversial. Methodology/Principal Findings: We used a co-immunoprecipitation assay to identify a previously undocumented binding site at 375-385 of DLC1 that predominantly interacted with the phosphotyrosine binding (PTB) domain of tensin2. DLC1-tensin2 interaction is completely abolished in a DLC1 mutant lacking this novel PTB binding site (DLC1ΔPTB). However, as demonstrated by immunofluorescence and co-immunoprecipitation, neither the focal adhesion localization nor the interaction with tensin1 and C-terminal tensin-like (cten) were affected. Interestingly, the functional significance of this novel site was exhibited by the partial reduction of the RhoGAP activity, which, in turn, attenuated the growth-suppressive activity of DLC1 upon its removal from DLC1. Conclusions/Significance: This study has provided new evidence that DLC1 also interacts with tensin2 in a PTB domain-dependent manner. In addition to properly localizing focal adhesions and preserving RhoGAP activity, DLC1 interaction with tensin2 through this novel focal adhesion binding site contributes to the growth-suppressive activity of DLC1. © 2009 Chan et al.published_or_final_versio